The structure, function and distribution of G protein coupled receptors have been studied with recent emphasis on the cannabinoid and GABA-B receptors. In collaboration with Andreas Zimmer, we have created transgenic mice in which either the CB1 or CB2 cannabinoid receptor has been knocked out and have characterized their phenotypes in order to gain a better understanding of the normal physiological role of these receptors and their recently discovered endogenous ligands, e.g., anandamide. The CB1 knockout mice seem outwardly normal except that they have a marked reduction in locomotor activity and significantly reduced life span. Delta-9-tetrahydrocannabinol (THC), the primary psychoactive ingredient of marihuana, acts primarily through the CB1 receptor. Many but not all CNS effects of THC are abolished in the CB1 knockouts.In collaboration with Janet Clark we had previously cloned rat and human cDNAs for a second GABA-B receptor, gb2. Together with collaborators at Merck we have shown that coexpression of the gb1 and gb2 receptors is required for functional GABA-B receptor activity in a number of heterologous expression systems. Thus, rather unexpectedly for this structural class of receptors, it appears that a heterodimer of gb1 and gb2 subunits is required for full act. - receptors, cannabinoid, GABA-B, transgenic, knockouts, pharmacology - Neither Human Subjects nor Human Tissues